ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.1885C>T (p.Pro629Ser) (rs200804638)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181226 SCV000233505 uncertain significance not provided 2019-01-10 criteria provided, single submitter clinical testing The P629S variant in the DSG2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The P629S variant is observed in 2/33,576 (0.01%) alleles from individuals of Latino background in large population cohorts (Lek et al., 2016). The P629S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret P629S as a variant of uncertain significance.
Invitae RCV000642309 SCV000763978 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2019-08-25 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 629 of the DSG2 protein (p.Pro629Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs200804638, ExAC 0.009%). This variant has not been reported in the literature in individuals with DSG2-related disease. ClinVar contains an entry for this variant (Variation ID: 199813). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000223710 SCV000919282 uncertain significance not specified 2018-11-05 criteria provided, single submitter clinical testing Variant summary: DSG2 c.1885C>T (p.Pro629Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 246854 control chromosomes (gnomAD and publication). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.1885C>T, has been reported in the literature in one individual affected with Alcoholic Cardiomyopathy (Ware_2018), together with the pathogenic TTN .43144_43147delCTGG (p.Leu14382ValfsTer2). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Health, Inc RCV001187863 SCV001354765 uncertain significance Cardiomyopathy 2020-11-17 criteria provided, single submitter clinical testing This missense variant replaces proline with serine at codon 629 of the DSG2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000223710 SCV000280083 uncertain significance not specified 2014-03-20 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Based on the data reviewed below, we would categorize this as a variant of unknown significance (VUS). This variant has not been reported in the scientific literature as a disease-causing mutation nor as a benign polymorphism to our knowledge. This is a non-conservative amino acid substitution in which a non-polar Proline is replaced by a neutral, polar Serine at a residue that is conserved across species. In silico analysis with PolyPhen-2 predicts the variant to be “probably damaging” with a score of 1.0. Only one missense variant at a nearby residue has been reported in HGMD in association with ARVC, which may or may not support the functional importance of this region of the protein: Gly638Arg (HGMD professional version as of January 17, 2014). The variant has not been seen in ~6200 individuals from population datasets. It is not listed in the NHLBI Exome Sequencing Project (ESP) dataset, which currently includes variant calls on ~4200 Caucasian and ~2000 African American individuals. The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. There is also no variant at codon 629 listed in 1000 genomes (as of March 20, 2014). The Pro629Ser variant is listed in dbSNP.

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